Power loss for multiallelic transmission/disequilibrium test when errors introduced: GAW11 simulated data

Abstract

Many researchers are considering the use of transmission/disequilibrium tests (TDT) for trios of genotypes (father, mother, child) as a method for localizing genes associated with complex diseases. We evaluate the effect of random errors (allele changes) in trios on the power to detect linkage. For a marker in the simulated data set, one allele is associated with the fictitious disease in a certain subpopulation. For the data as given (no errors), our power to detect linkage using the multiallelic TDT (TDT(mhet)) is 68% (critical p-value set at 0.0001). We introduce errors into trios at various rates (1%, 5%, or 10%), remove only trios displaying mendelian inconsistencies, and recalculate power to detect linkage. Our principal finding is that there is power loss to detect linkage with the TDT(mhet) when errors are introduced. We observe power losses of 8%, 16%, and 48% for error rates of 1%, 5%, and 10%, respectively. To determine the source of the power loss, we perform Monte Carlo simulations. At the 1% and 5% rates, we conclude that power loss is due primarily to loss in sample size. At the 10% rate, we observe substantial power loss due to error introduction in addition to sample size reduction. We also determine, given a particular error rate, the probability that we detect errors if we use only mendelian consistency as a check. We find that the mean detection rates for the data sets with 1%, 5%, or 10% error rates are 58%, 60%, and 62%, respectively. As a result, the apparent error rate appears to be almost half the true error rate. Based on these results, we recommend that researchers maintain error rates below 5% when using the TDT(mhet) for linkage, use additional methods beyond mendelian consistency checks when searching for errors in their data, and modify sample size calculations when accounting for errors in their genotype data.